This application is a 371 of PCT/US99/28440 filed Dec. 2, 1999.
The present invention relates to a process for preparing optically active xcex1-hydroxy acids and derivatives thereof. xcex1-Hydroxy acids are important intermediates for synthesis of organic compounds in pharmaceutical and industrial applications. More particularly, the present invention relates to an enantioselective synthesis for xcex1-hydroxy acids by employing 10-camphorsulfonamide as a chiral auxiliary through 1,3-dioxolanones.
Optically active xcex1-hydroxy acids are structural subunits of many natural products, such as motuportin, integerrimine, monocrotaline, and eremantholide A. xcex1-Hydroxy acids and their derivatives are important intermediates for the synthesis of organic compounds in pharmaceutical and industrial applications. A number of useful synthetic methods for the preparation of enantiomertically pure xcex1-branched xcex1-hydroxy acids have been developed. Generally, optically active xcex1-hydroxy acids are obtained through microbial methods, enzymatic syntheses and enantioselective syntheses using chiral auxiliaries.
Microbial methods utilizes microorganism to convert the precursors of xcex1-hydroxy acids, such as oxo- or hydroxy-containing compounds, to produce xcex1-hydroxy acids and derivatives thereof. For example, U.S. Pat. No. 5,326,702 discloses a process for biologically producing an xcex1-hydroxyamide or an xcex1-hydroxy acid, comprising reacting an xcex1-hydroxynitrile or an aldehyde with a microorganism which produces an amide or acid from the corresponding xcex1-hydroxynitrile, in the presence of a sulfite ion, a disulfite ion or a dithionite ion. The related prior art such as U.S. Pat. Nos. 5,371,014, 5,508,181, 5,756,306 and 5,273,895 can also be incorporated herein for reference. However, when using microbial methods, it is difficult to isolate the product from the fermentation broth. The purification for the product is complex and very expensive. Also, the fermentation process usually generates a large amount of waste effluent which harm the environment. An additional treatment process is required and it is not economical.
U.S. Pat. No. 5,098,841 discloses a process for the preparation of the enantiomers of 2-hydroxy-4-phenylbutyric acid, comprising reducing 2-oxo-4-phenyl-butyric acid with the enzyme lactate dehydroaenases in the presence of an electron donor and an enzyme/substrate system. The related prior art utilizing enzymatic syntheses, such as U.S. Pat. Nos. 5,273,895, 5,523,223, 5,686,275 and 5,770,410, can also be incorporated herein for reference. However, purified enzymes are expensive. Therefore, enzymatic syntheses need a stoichiometric amount of expensive cofactors. In addition, the optical purity of an enantioselective product obtained from enzymatic synthesis is highly substrate dependent.
U.S. Pat. Nos. 5,488,131 discloses a method for synthesis of compounds of predetermined chirality that are useful in asymmetric synthesis, comprising the acylation of an enantiomer of pseudoephedrine and then the alkylation of the xcex1-carbon of the adduct, wherein the alkylation proceeds in a stereoselective manner and is directed by the chiral auxiliary pseudoephedrine. The related prior art utilizing enantioselective syntheses using chiral auxiliary, such as U.S. Pat. Nos. 4,983,766, 5,512,682, 5,512,688, 5,516,930, 5,578,730, 5,760,237 and 5,919,949 can also be incorporated therein for reference. There are still some disadvantages when utilizing those enantioselective syntheses. For example, the enantioselectivity of the product is low; chiral auxiliary is very expensive and is not available for large scale production; and the recovery of chiral auxiliary is difficult. Therefore, there remains some room for the development of more efficient methods to produce an optically active compound.
By use of the enantioselectivity of 10-camphorsulfonamide, we have found an enantioselective synthetic method for xcex1-hydroxy acids and derivative thereof through 1,3-dioxolanones by employing 10-camphorsulfonamide as a chiral auxiliary. The process of the present invention does not have the disadvantages encountered in the prior art and has several advantages such as high enantioselectivity of products and high chemical yields. Moreover, both (S) form and (R) form of 10-camphorsulfonamide chiral auxiliaries are commercially available for large scale production and such chiral auxiliaries can be easily recovered in high yield in the process per se. Therefore, the process of the present invention is highly enantioselective, efficient, economic, and easy to do.
The present invention relates to a process for preparing optically active xcex1-hydroxy acids and derivatives thereof through 1,3-dioxolanones by employing 10-camphorsulfonamide as a chiral auxiliary. The 1,3-dioxolanones are prepared by the catalyzed condensation of a dialkoxy acetal which is derived from the chiral auxiliary, 10-camphorsulfonamide, by treating with xcex1-hydroxy acids. The 1,3-dioxolanones are enantioselective and therefore can be further used to produce optically active compounds such as xcex1-hydroxy acids and derivatives thereof. The 1,3-dioxolanones are subjected to alkylation and then either to alcoholysis or to hydrolysis to produce mono- and disubstituted xcex1-hydroxy acids and derivatives thereof and 10-camphorsulfonamide. 10-camphorsulfonamide can be easily recovered.
The present invention relates to an enantioselective synthesis for xcex1-hydroxy acids through 1,3-dioxolanones by employing 10-camphorsulfonamide as a chiral auxiliary.
Generally, the process of the present invention for preparing optically active xcex1-hydroxy acids comprises steps of
(a) reacting 10-camphorsulfonamide of formula I 
wherein R1 and R2 are the same or different and are each independently H or C1-6 alkyl,
with alkoxy-substituted alkane to form dialkoxy acetal of formula II 
wherein R1 and R2 are the same or different and are each independently H or C1-6 alkyl, R3 and R4 are the same or different and are each independently C1-4 alkyl;
(b) reacting the dialkoxy acetal of formula II with an xcex1-hydroxy acid having the formula 
wherein R5 is H, C1-16 alkyl, or unsubstituted or substituted phenyl, to form 1,3-dioxolanones of formula III 
wherein R1 and R2 are the same or different and are each independently H or C1-6 alkyl, and R5 is H, C1-16 alkyl, or unsubstituted or substituted phenyl;
(c) reacting the 1,3-dioxolanones of formula III with alkylation reagents to form alkylated 1,3-dioxolanones of formula IV 
wherein R1 and R2 are the same or different and are each independently H or C1-6 alkyl, R5 is H, C1-16 alkyl, or unsubstituted or substituted phenyl, and R6 is C1-8 alkyl, C2-7 alkenyl or unsubstituted or substituted benzyl;
(d) subjecting the alkylated 1,3-dioxolanones of formula IV to either
(i) alcoholysis, when R5 is H, to form 10-camphorsulfonamide and xcex1-hydroxy acids derivatives of formula V 
wherein R7 is C1-6 alkyl, and R6 is C1-8 alkyl, C2-7 alkenyl or unsubstituted or substituted benzyl, or
(ii) hydrolysis, when R5 is C1-16 alkyl or unsubstituted or substituted phenyl, to form 10-camphorsulfonamide and xcex1-hydroxy acids of formula VI 
wherein R5 is H, C1-16 alkyl, or unsubstituted or substituted phenyl, and R6 is C1-8 alkyl, C2-7 alkenyl or unsubstituted or substituted benzyl.
The starting material, 10-camphorsulfonamide of formula I, for the process of the present invention is generally known and available in the art. In step (a), the 10-camphorsulfonamide of formula I reacts with alkoxy-substituted alkane to form a dialkoxy acetal of formula II. The reaction can be conducted in the absence or presence of catalysts and solvents known to persons skilled in the art. Catalysts such as p-toluene sulfonic acid (p-TSA) and solvents such as alcohols, for example, methanol, are commonly used. In the preferred embodiment of the present invention, the alkoxy-substituted alkane used is (CH3O)3CH.
In step (b), the dialkoxy acetal of formula II produced from step (a) is subjected to Lewis acid-catalyzed condensation with an xcex1-hydroxy acid having the formula R5C(OH)COOH, wherein R5 is H, C1-16 alkyl, or unsubstituted or substituted phenyl, to produce 1,3-dioxolanones of formula III. The reaction conditions for Lewis acid-catalyzed condensation is known in the state of art. Reference can be made to sources such as Farines, M.; Soulier, J. Bull. Soc. Chim. Fr. 1970, 332; Petasis, N. A.; Lu, S.-P. J. Am. Chem. Soc. 1995, 117,6394; Pearson, W. H.; Cheng, M.-C. J. Org. Chem. 1987, 52, 1353; and Hoye, T. R.; Peterson, B. H.; Miller, J. D. J. Org. Chem. 1987, 52, 1351. In the embodiment of the present invention, the dialkoxy acetal is reacted with xcex1-hydroxy acid, preferably, glycolic acid, lactic acid and mandelic acid, under an inert gas, at a temperature from about xe2x88x9235xc2x0 C. to about xe2x88x9260xc2x0 C., in the presence of ethers as the solvent. The Lewis acid used in the preferred embodiment of the present invention is BF3.OEt2.
Due to the enantioselectivity of 10-camphorsulfonamide of formula I, the product 1,3-dioxolanones of formula III are also enantioselective. Therefore, the enantioselective 1,3-dioxolanones of formula III is very useful to prepare optically active compounds such as xcex1-hydroxy acids and derivatives thereof.
When R5 is H, the reaction of step (b) may produce a small amount of by-product of 1,3-dioxolanones having formula IIIa 
wherein R1 and R2 are the same of different and are each independently H or C1-6 alkyl. The 1,3-dioxolanones of formulae III and IIIa are diastereomeric chiral compounds. Pure 1,3-dioxolanones of formula III can be obtained by recrystallization, or separated from their minor isomers of the 1,3-dioxolanones of formula IIIa by column chromatography. The conditions for recrystallization and column chromatography are well known to persons skilled in the art.
When R5 is C1-16 alkyl or unsubstituted or substituted phenyl, the 1,3-dioxolanones of formula III are single products. The stereochemistry of 1,3-dioxolanones can be confirmed by known methods commonly used in the art such as X-ray crystallographic analysis and nuclear overhauser effect (NOE) experiments.
In the alkylation of step (c), 1,3-dioxolanones of formula III are reacted with alkylation reagents such as R6X wherein R6 is C1-C8 alkyl, C2-C7 alkenyl or unsubstituted or substituted benzyl, and X is a leaving group, to form the alkylated 1,3-dioxolanones of formula IV. Preferably, the alkylation reagent is a halide or sulfonate. The alkylation is conducted under a temperature from xe2x88x92110xc2x0 C. to room temperature, preferably from xe2x88x92100xc2x0 C. to 0xc2x0 C., more preferably from xe2x88x92100xc2x0 C. to 45xc2x0 C., most preferably from xe2x88x92100xc2x0 C. to xe2x88x9278xc2x0 C., in the presence of a strong base, such as lithium diisopropylamide (LDA), in the absence or presence of solvents. It is found that when deprotonation and the addition of an alkylation reagent were conducted at xe2x88x92100xc2x0 C. then increased the temperature to xe2x88x9278xc2x0 C., the diastereoselectivity and the yield of the products can be improved. In the alkylation, no diastereoisomers are detected by 400 MHz 1H NMR measurement. The alkylated 1,3-dioxolanones of formulae IV have excellent diastereoselectivity. The stereochemistry of the alkylated 1,3-dioxolanones of formulae IV can be detected by conventional manners such as X-ray crystallographic analysis.
In step (d), the alkylated 1,3-dioxolanones of formula IV can be further subjected to alcoholysis or hydrolysis to produce xcex1-hydroxy acids of formula VI and derivatives thereof of formula V. When R5 is H, the alkylated products is subject to alcoholysis of step (i). In the preferred embodiment of the present invention, the alcoholysis is conducted by heating the alkylated 1,3-dioxolanones of formula IV with anhydrous hydrogen chloride in absolute alcohols with formula R7OH wherein R7 is C1-6 alkyl, such as ethanol. In alcoholysis the 10-camphorsulfonamide of formula I is also produced. The, xcex1-hydroxy acids derivatives of formula VI can be separated and purified by a conventional manner such as column chromatograph). 10-Camphorsulfonamide can therefore be recovered. The reaction scheme of step (d)(i) is shown as follows, 
wherein RI and R2 are the same or different and are each independently H or C1-6 alkyl, R5 is H, R6 is C1-8 alkyl, C2-7 alkenyl or unsubstituted or substituted benzyl, and R7 is C1-6 alkyl.
When R5 is C1-16 alkyl or unsubstituted or substituted phenyl, the alkylated 1,3-dioxolanones of formula IV are subject to the hydrolysis of step (ii). The hydrolysis conditions are conventional in the state of the art. In the preferred embodiment of the present invention, the hydrolysis is conducted by reacting the alkylated 1,3-dioxolanones of formula IV with a strong base such as NaOH in the presence of alcohols, such as methanol, as the solvent. In hydrolysis, the 10-camphorsulfonamide of formula I is also produced, 10-Camphorsulfonamide can be separated by a conventional method such as extraction and recovered. The purification of xcex1-hydroxy acids can be conducted by concentration. The reaction scheme of step (d)(ii) is shown as follows, 
wherein R1 and R2 are the same or different and are each independently H or C1-6 alkyl, R5 is C1-16 alkyl or unsubstituted or substituted phenyl, and R6 is C1-8 alkyl, C2-7 alkenyl or unsubstituted or substituted benzyl.
The xcex1-hydroxy acids and derivatives thereof are important intermediates for synthesis of optically active organic compounds in pharmaceutical and industrial applications.